pentostatin and Immunologic-Deficiency-Syndromes

Hairy cell leukaemia is a rare chronic lymphoproliferative disease, characterized by splenomegaly, pancytopenia and recurrent infection. The characteristic 'hairy cells', present in the peripheral blood and bone marrow, are the hallmark of this leukaemia. The disease has a chronic, progressive course, and the majority of patients afflicted by it require therapy. The most common reason to initiate treatment is neutropenia with or without associated infectious complications, or the development of severe thrombocytopenia. Therapeutic options in hairy cell leukaemia include splenectomy, interferon administration, or the use of chemotherapeutic agents such as pentostatin (2'-deoxycoformycin) and 2-chlorodeoxyadenosine. Splenectomy is still indicated in the treatment of young patients with significant splenomegaly and only minimal bone marrow involvement. Interferon treatment induces remission in approximately 90% of patients with hairy cell leukaemia, but complete remission is obtained in only 5-10%. The development of antibodies against interferon was initially considered a major problem, but longer follow-up of patients who developed antibodies has shown that it is transient and does not have a significant impact on the overall response to treatment. Pentostatin induces complete remission in 60-70% of patients and partial remission in 20-40%. 2-Chlorodeoxyadenosine is a very promising drug in the treatment of this rare leukaemia, inducing long-lasting complete remission in approximately 80% of patients. While interferon does not cure the disease, it is possible that a subset of patients treated with pentostatin or 2-chlorodeoxyadenosine are cured. Longer follow-up of these patients will determine whether this is true.

Topics: Adult; Cladribine; Clinical Trials as Topic; Female; Humans; Immunologic Deficiency Syndromes; Immunologic Factors; Interferon-alpha; Leukemia, Hairy Cell; Male; Middle Aged; Pancytopenia; Pentostatin; Prognosis; Remission Induction; Splenectomy; Splenomegaly; Treatment Outcome

Hairy-cell leukemia is an unusual chronic lymphoid leukemia with distinctive clinical and pathological features. The management of this disorder has been revolutionized in the last decade with the discovery of the efficacy of alpha interferon and the inhibitors of adenosine metabolism, deoxycoformycin and chlorodeoxyadenosine. The best treatment protocol for hairy-cell leukemia has not yet been defined. Patients may still die from their disease, particularly in the early phases of treatment. Conversely, some patients appear not to require treatment and others respond well to splenectomy and need no further therapy. An individualized clinical approach is recommended, with a role for splenectomy in the patient with cytopenia and a relatively low number of hairy cells in the bone marrow. The first line drug treatment remains interferon alpha given for 12-18 months, following which the patient is observed for clinical relapse. Deoxycoformycin remains a useful experimental agent but cannot be recommended for routine clinical use until issues of long term toxicity are resolved. Chlorodeoxyadenosine is a very promising experimental drug, but confirmation of the early data in larger group trials is required. Similarly the adjunctive use of granulocyte colony stimulating factor appears useful, but will need further study in larger groups of patients. There is little or no role for alkylating agents or more intensive chemotherapy in the modern management of hairy-cell leukemia.

Topics: 2-Chloroadenosine; Antibody Formation; Antineoplastic Agents; Cladribine; Combined Modality Therapy; Deoxyadenosines; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Immunologic Deficiency Syndromes; Immunologic Factors; Interferon Type I; Leukemia, Hairy Cell; Pentostatin; Remission Induction; Retrospective Studies; Splenectomy

Topics: Adenine; Adenosine Deaminase; Adenosine Deaminase Inhibitors; Animals; Cells, Cultured; Coformycin; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Pentostatin; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Purine-Pyrimidine Metabolism, Inborn Errors

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Animals; Child; Child, Preschool; Coformycin; Erythrocytes; Female; Humans; Immunologic Deficiency Syndromes; Leukemia; Male; Nucleoside Deaminases; Pentostatin; Pentosyltransferases; Purine-Nucleoside Phosphorylase; Transcobalamins

Deficiencies of two enzymes that catalyze sequential reactions in the purine catabolic pathway have been causally associated with immunodeficiency states. Adenosine deaminase (ADA) deficiency results in severe combined immunodeficiency disease, while purine nucleoside phosphorylase (PNP) deficiency results in an isolated T-cell defect. Recent work in this area has provided major new insights into the molecular pathology of these syndromes. Deoxyadenosine and deoxyguanosine, substrates that accumulate in ADA and deoxyguanosine, substrates that accumulate in ADA and PNP deficiency, respectively, appear to be selectively phosphorylated by lymphoid cells to the corresponding deoxynucleoside triphosphate, resulting in inhibition of DNA synthesis in these cells. Both deoxynucleosides are far more toxic to cultured T lymphoblasts than to B lymphoblasts. Adenosine and deoxyadenosine may have additional lymphotoxic effects mediated by inhibition of essential methylation reactions. These observations help to explain the immunologic manifestations of ADA and PNP deficiency. Perhaps more important, they lay the foundation for the use of deoxynucleosides or enzyme inhibitors, or both, as selective immunosuppressive and chemotherapeutic agents.

Topics: 5'-Nucleotidase; Adenosine Deaminase; Animals; Coformycin; Cytotoxicity, Immunologic; Deoxyadenosines; Deoxyribonucleotides; Humans; Immunologic Deficiency Syndromes; Lymphocytes; Nucleoside Deaminases; Nucleotidases; Pentostatin; Pentosyltransferases; Purine-Nucleoside Phosphorylase; T-Lymphocytes

Hairy-cell leukemia is an unusual chronic lymphoid leukemia with distinctive clinical and pathological features. The management of this disorder has been revolutionized in the last decade with the discovery of the efficacy of alpha interferon and the inhibitors of adenosine metabolism, deoxycoformycin and chlorodeoxyadenosine. The best treatment protocol for hairy-cell leukemia has not yet been defined. Patients may still die from their disease, particularly in the early phases of treatment. Conversely, some patients appear not to require treatment and others respond well to splenectomy and need no further therapy. An individualized clinical approach is recommended, with a role for splenectomy in the patient with cytopenia and a relatively low number of hairy cells in the bone marrow. The first line drug treatment remains interferon alpha given for 12-18 months, following which the patient is observed for clinical relapse. Deoxycoformycin remains a useful experimental agent but cannot be recommended for routine clinical use until issues of long term toxicity are resolved. Chlorodeoxyadenosine is a very promising experimental drug, but confirmation of the early data in larger group trials is required. Similarly the adjunctive use of granulocyte colony stimulating factor appears useful, but will need further study in larger groups of patients. There is little or no role for alkylating agents or more intensive chemotherapy in the modern management of hairy-cell leukemia.

Topics: 2-Chloroadenosine; Antibody Formation; Antineoplastic Agents; Cladribine; Combined Modality Therapy; Deoxyadenosines; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Immunologic Deficiency Syndromes; Immunologic Factors; Interferon Type I; Leukemia, Hairy Cell; Pentostatin; Remission Induction; Retrospective Studies; Splenectomy

Nijmegen breakage syndrome (NBS) is characterized by growth retardation, microcephaly, mental retardation, immunodeficiency, and predisposition to malignancies, especially B-cell lymphomas. In contrast, leukemia is rare. A 23-year-old NBS patient presented with anemia, thrombocytopenia, and hyperlymphocytosis. The diagnosis of T-cell prolymphocytic leukemia (T-PLL) was confirmed by cytological and immunological assays (TdT(-), CD2(+), CD5(+), CD3m, and CD7(+)). Biological assays also showed a hemolytic anemia and a clotting factor V decrease. The patient was first treated by methylprednisone for 3 weeks. During this period the lymphocyte count decreased. The simultaneous normalization of the hemolysis and of factor V suggested that both could be related to T-PLL. Since T-PLL is refractory to conventional therapies with a poor prognosis, an intensive chemotherapy such as 2'-deoxycoformycin with anti-CDw52 monoclonal antibodies is usually favored. In the present case, however, because of the specific context (i.e., NBS-induced immunodepression, severe hemolytic anemia, and acquired factor V deficiency), he received pentostatin weekly during 1 month and in maintenance during 6 months. At last follow-up (7 months) he showed a persistent control of the lymphocytosis with no side effect.

Topics: Adolescent; Anemia, Hemolytic, Autoimmune; Antibiotics, Antineoplastic; Cytogenetic Analysis; Factor V Deficiency; Genes, Recessive; Glucocorticoids; Growth Disorders; Humans; Immunologic Deficiency Syndromes; Infant, Newborn; Intellectual Disability; Leukemia, Prolymphocytic; Leukemia, T-Cell; Male; Methylprednisolone; Microcephaly; Pentostatin; Syndrome

The effect of deoxyadenosine (dAdo) with deoxycoformycin on the induction of 2',5'-oligoadenylate synthetase by interferon was investigated. After semi-purification through poly(I):poly(C) gel, the activity was similar in control and dAdo-treated cells. However, the activity in the crude extract decreased with rising concentrations of dAdo. On the other hand, the level of 2'-phosphodiesterase, which is also induced by interferon and degrades 2',5'-oligoadenylate, showed no significant change after dAdo treatment. Thus, the crude extract was speculated to contain an inhibitor of 2',5'-oligoadenylate synthetase. Further characterization of the inhibitor revealed that inhibition was not due to dATP accumulation in cells.

Topics: 2',5'-Oligoadenylate Synthetase; Adenosine Deaminase; Cell Line; Coformycin; Deoxyadenine Nucleotides; Deoxyadenosines; Enzyme Induction; Exoribonucleases; Humans; Immunologic Deficiency Syndromes; Interferon Type I; Pentostatin; Ribonucleosides; T-Lymphocytes

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Blood Transfusion; Cell Line; Coformycin; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infant; Lymphocytes; Lymphoproliferative Disorders; Male; Mutation; Nucleoside Deaminases; Pentostatin; RNA, Messenger

High levels of dATP and dADP, accompanied by ATP depletion, were found in the platelets of two ADA-deficient children with severe combined immunodeficiency (SCID). In vitro studies demonstrated that even normal platelets had the ability to make dATP from deoxyadenosine (dAR) under physiological conditions. This capability was greatly enhanced by conditions simulating ADA deficiency. These results question whether the platelet has a specific role in the normal immune response.

Topics: Adenosine Deaminase; Adenosine Triphosphate; Blood Platelets; Coformycin; Deoxyadenine Nucleotides; Humans; Immunologic Deficiency Syndromes; Nucleoside Deaminases; Nucleotides; Pentostatin

Low ATP/ADP ratios have been reported consistently for nucleotide levels of mononuclear cells separated from peripheral blood by conventional techniques. We have established that these low values (mean 2.3:1) were not due to cell damage or poor viability, but resulted from heavy platelet contamination, which is unavoidable when heparinized blood is used. The results reflect the low ATP/ADP ratios (mean 1.6:1) characteristic of platelets. Platelet-free extracts from defibrinated blood had very high ATP/ADP ratios (mean 17.4:1). The initial finding of detectable amounts of deoxy-ATP and deoxy-GTP in mononuclear cells from children with two distinct inherited immunodeficiency disorders [adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency respectively] many have been due to contamination by nucleated erythrocytes as well as platelets in non-defibrinated preparations. Defibrination before nucleotide extraction of mononuclear cells from a patient with T-cell leukaemic/lymphoma treated with the ADA inhibitor deoxycoformycin enabled the demonstration of grossly raised deoxy-ATP levels relative to deoxy-ADP levels (ratio 16.1:1), associated with severe ATP depletion. This reciprocal relationship between ATP and dATP was found by us previously in the erythrocytes in inherited ADA deficiency. These findings underline the importance of extracts uncontaminated by platelets, or nucleated erythrocytes, in the evaluation of lymphocyte nucleotide levels in inherited or acquired immunodeficiency syndromes.

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Adenosine Diphosphate; Adenosine Triphosphate; Blood Platelets; Cell Separation; Child; Coformycin; Deoxyadenine Nucleotides; Deoxyguanine Nucleotides; Humans; Immunologic Deficiency Syndromes; Lymphocytes; Pentostatin; Purine-Nucleoside Phosphorylase

An in vivo murine model for immunodeficiency of both B and T cells is produced by continuous intraperitoneal infusion of 2'-deoxycoformycin (DCF), a specific tightly binding inhibitor of adenosine deaminase (ADase; adenosine aminohydrolase, EC 3.5.4.4). After DCF infusion, ADase of thymus, spleen, and lymph nodes was inhibited to varying degrees ranging from 57% to 100%. Immunodeficiency under these conditions was indicated by: (i) a striking decrease in lymphocyte response to the T-cell mitogens concanavalin A and phytohemagglutinin; (ii) an impairment of delayed hypersensitivity measured by the footpad reaction; (iii) a decrease in antibody production measured in both in vivo and in vitro plaque-forming cell assay; (iv) a significant prolongation of mouse skin allograft survival after transplantation into the C57BL/6J (H-2b) strain of skin from BALB/c (H-2d) mice; and (v) a marked lymphopenia. Histological examination indicated lymphoid degeneration in the thymus, lymph nodes, and spleen with no alterations in other tissues including bone marrow, kidney, lung, gastrointestinal tract, and liver except for the occurrence of hepatitis. A decrease in the number of Thy-1-positive cells in both spleen and lymph nodes further supported the fact of cytotoxicity of DCF to T cells. Anorexia and weight loss were observed within 5 days of continuous DCF infusion at 0.4 mg/kg body weight per day. These data indicate that this method provides an experimental model for future studies on the biochemical mechanisms responsible for the genetically determined severe combined immunodeficiency disease in man.

Topics: Adenosine; Adenosine Deaminase; Adenosine Deaminase Inhibitors; Animals; Antibody Formation; B-Lymphocytes; Coformycin; Disease Models, Animal; Immunity, Cellular; Immunologic Deficiency Syndromes; Mice; Nucleoside Deaminases; Pentostatin; Ribonucleosides; T-Lymphocytes